1. Field of the Invention
The present invention relates to a method for producing L-ascorbic acid 2-phosphates.
2. Description of Related Arts
L-Ascorbic acid (Vitamin C) is used widely in various fields such as drugs, foodstuffs, cosmetics and feedstuffs. L-Ascorbic acid is a reductive substance and has disadvantages that it has a poor stability because it is susceptible to heat and light and readily undergoes oxidation with oxygen in the air particularly when it is in a free state.
The instability is known to be due to ene-diol groups at the 2- and 3-positions of L-ascorbic acid structure. Therefore, the reductivity of L-ascorbic acid can be prevented by introducing appropriate substituents at one or both hydroxyl groups thereof, and hence the above-described defects of the acid can be removed.
Accordingly, various ascorbic acid derivatives have heretofore been proposed. It has been confirmed that among the conventional L-ascorbic acid derivatives, those derivatives which are derived by esterifying the hydroxyl group at the 2-position of L-ascrobic acid with phosphoric acid, i.e., L-ascorbic acid 2- phosphates, are readily hydrolyzed in vivo and exhibit vitamin C activity and are stable as well (cf. E. Cutolo and A. Larizza, Gazz. Chim. Ital. 91, 964 (1961)).
As for the method for the production of L-ascorbic acid 2-phosphates, there have heretofore been known those methods in which L-ascorbic acid or its salts or L-ascrobic acid derivatives of which the hydroxyl groups at the 5- and 6-positions have each been protected with a protective group are reacted with, for instance, phosphoric halide (cf. E. Cutolo and A. Larizza, Gazz. Chim. Ital. 91, 964 (1961), Chem. Pharm. Bull. 19(7) 1433 (1971), U.S. Pat. No. 3,671,549, and German Patent 1,805,958).
However, the above-described methods are disadvantageous as an industrial method because according to them, the hydroxyl groups at the 3-, 5- or 6-position are phosphorylated at the same time, thus producing several kinds of homologues and 2-pyrophosphates as by-produots in addition to the objective compounds to lower the yields of the objective compounds, and it is very difficult to separate the by-products, with the result that there are required very complicated purification steps and also a large amount of chemicals and many days for the separation, thus leading to increase in the production cost.
U.S. Pat. No. 3,858,848 discloses an improved method for the production of L-ascorbic acid 2-phosphate with its selectivity. Although the patent referred to a method for the synthesis of L-ascorbic acid 3-phosphate and it was considered at that time that the 3-position of L-ascorbic acid was esterified with phosphoric acid, it has recently been confirmed that what is actually esterified with phosphoric acid is the 2-position of L-ascorbic acid.
The above-described method is to react 5,6-isopropylidene-L-ascorbic acid or L-ascorbic acid with a phosphoric halide in a specific solvent (such as water, or a mixed solvent composed of water and acetone, dimethylformamide or trimethylphosphoric acid) in the presence of a base at temperature not higher than room temperature. More particularly, L-ascorbic derivative of which the hydroxyl groups at the 5- and 6-positions have been protected with acetone under acidic conditions (i.e., 5,6-isopropylidene-L-ascorbic acid) or L-ascorbic acid is dissolved in a mixed solvent composed of water and pyridine or a mixture of water and calcium hydroxide, and phosphorus oxychloride is added dropwise to the resulting solution or mixture at a temperature not higher than 0.degree. C., and the reaction is continued at the same temperature for 90 minutes (reaction ratios: 94.5% and 70.6%, respectively). Then, the reaction mixture is treated with Amberlite Resin IR-120 (H.sup.+ -form) at room temperature to desalt the product, followed by neutralization with magnesium oxide, removal of the solvent by distillation, dropwise addition of ethanol to the residue to obtain white powder of magnesium salt of L-ascorbic acid 2-phosphate, which is recrylstallized from water-ethanol (yields: 75.1% and 55.3%, respectively).
U.S. Pat. No. 4,179,445 discloses another improved method in which 5,6-isopropylidene-L-ascorbic acid, a phosphorus oxyhalide of general formula POX.sub.3 (wherein X is a halogen atom) and a specific solvent (a mixed solvent composed of water and a tertiary amine) are mixed with each other and the mixture is kept at pH 13 or higher to react. More particularly, 5,6-isopropylidene-L-ascorbic acid is dissolved in a mixed solvent composed of water and pyridine, and phosphorus oxychloride is added dropwise to the mixture at -10.degree. C. to +10.degree. C. In this case, an aqueous solution of 10M sodium hydroxide is added dropwise to the mixture while stirring in order to carry out the reaction in a higher pH range (e.g., about pH 13). After completion of the reaction, the reaction mixture is cooled to room temperature, treated with a strongly acidic cation exchange resin (H.sup.+ -form) for desalting and purification, followed by neutralization with magnesium oxide and removal of the solvent by distillation and dropwise addition of ethanol to the residue to give white powder of magnesium salt of L-ascorbic acid 2-phosphate, which is collected by filtration (yield: 86%).
However, what is common among the above-described improved methods is that the phosphorylation reaction is carried out at a temperature of not higher than 10.degree. C., mostly not higher than 5.degree. C. and various operations for overall steps of production are conducted while keeping ambient temperature at low temperatures which are not higher than room temperature. For this reason, a relatively large amount of by-products, i.e., bis(L-ascorbic acid) 2,2'-phosphate, bis(L-ascorbic acid) 2,3'-phosphate, bis(L-ascorbic acid) 3,3'-phosphate, L-ascorbic acid 3-phosphate and the like, are produced. These by-products have been abandoned after they were separated from the objective compounds in purification steps even though they occupy a large amount, e.g., 20 to 30%, of the total products of the reaction concerned.
As the result, the yield of the objective L-ascorbic acid 2-phosphate remains at a low level and means for separating and purifying the objective substance are very complicated and unsatisfactory as an industrial production method.